[3] The county is located just east of the Mississippi Delta in the northern part of the state.

Following forced removal of most of the historic Chickasaw tribe to territory west of the Mississippi River, Panola County was established February 9, 1836, by the state legislature.

It is one of the twelve large northern Mississippi counties created that year from the territory of the Chickasaw Cession of 1832.

The original act defined its limits as follows: Beginning at the point where the line between ranges 9 and 10 strikes the center of section 6, and running thence south with the said range line, and from its termination in a direct line to the northern boundary of Tallahatchie County and thence along the northern boundary of Tallahatchie and Yalobusha counties, to the center of range 5 west; thence north through the center of range 5 west, according to the sectional lines, to the center of township six; thence west through the center of township six, according to the sectional lines, to the beginning.On February 1, 1877, when Quitman County was organized by the legislature, it took a small fraction of Panola's southwestern area, reducing Panola from an area of 756 square miles (1,960 km2) to its present land surface of 705 square miles (1,830 km2).

Starting in 1803, sixteenth sections in each township in Mississippi were established for school purposes.

There was no public education, and only wealthier families hired tutors or sent their sons to seminaries or academies.

Through the antebellum period, the state generally forbade education of slaves and free people of color.

By 1840, four small private schools with a combined student population of 92 pupils were operating in the county.

The proposed scheme received considerable discussion and was finally incorporated by the state legislature (March 4, 1846) into "An Act to establish a System of Common Schools.

"[10][11] To a large degree, this act was passed because A.G. Brown, a candidate for Mississippi governor, decided to make the establishment of a general school system a campaign issue.

"[5] Although the Act had proved to be of little assistance in Panola County, progress was being made for wealthier white students.

This census (unpublished returns) recorded that 18 individuals stated their occupation as educators or teachers.

Several years later, the facility was moved to Peach Creek, where the school was informally known as the "Greasy Smith Schoolhouse," being named for the local village blacksmith.

[16] As of the 2020 United States Census, there were 33,208 people, 12,488 households, and 8,512 families residing in the county.